Substantial evidence implicates the dopaminergic midbrain (hereafter midbrain) both in motivation and reward processing and in learning and memory. Abnormalities in the dopamine (DA) system characterize many disorders associated both with anhedonia (the inability to experience pleasure) and with disturbances of learning and memory, notably depression, schizophrenia, and Parkinson's disease. Current treatment options are limited to pharmacotherapy - which often causes adverse side effects - and psychotherapy, which is time consuming, effortful, and costly. In most cases, neither treatment fully alleviates the symptoms. The NIMH Strategic Plan demands new treatment development, emphasizing approaches that are efficient, effective, and safe enough for early interventions. The current application describes a novel intervention - cognitive neurostimulation - in which cognition is used to regulate neuromodulatory brain regions. Real-time fMRI (rt-fMRI) neurofeedback is here leveraged to 1) improve sustained activation in the midbrain during motivated states and 2) yoke the flow of stimuli presentation to midbrain activation in a memory paradigm. The proposed studies investigate 1) behavioral, genetic, and neural determinants of midbrain self-activation in individuals with anhedonia and 2) a causal role for the midbrain in declarative memory formation in individuals with and without anhedonia. Aim 1 will examine 1) the ability of individuals with anhedonia to self- activate the midbrain during motivation; 2) genetic variations in DA availability and self-activation success; 3) resultant changes in motivation and memory; and 4) lasting symptom improvement. This experiment will test the hypotheses that 1) individuals with anhedonia will be initially poor at midbrain self-activation; 2 they will improve with rt-fMRI training; 3) midbrain self-activation positively correlates with genetically determined DA availability; 4) self-activation will predict motivation and memory; and 5) will produce lasting symptom improvement. Aim 2 will investigate 1) a causal role for the midbrain in declarative memory in individuals with and without anhedonia; and 2) examine genetic variations in DA availability and its relationship to declarative memory. This experiment will test the hypotheses that 1) midbrain activation plays a causal role in declarative memory formation; 2) genetically determined DA availability predicts successful declarative memory formation; and 3) individuals with anhedonia will show impaired memory relative to healthy controls. Summary: The goal of this application is to use rt-fMRI of midbrain activity to examine 1) the utility of using cognitive neurostimulation as a microintervention in individuals with anhedonia and 2) a causal role of the DA system in declarative memory formation in individuals with and without anhedonia. Understanding the determinants and consequences of midbrain self-activation will confer tools for improving motivation, working memory, attention, and learning and memory in healthy individuals. The development of a physiological, non-invasive intervention for DA dysfunction is applicable across diagnostic categories and holds promise for preemptive treatment.